α2-adrenergic receptors are located on pre-junctional terminals in the central nervous system where they inhibit the release of norepinephrine in the form of negative feedback. They are further located postsynaptically on the vascular smooth muscle cells of certain blood vessels, such as those found in skin arterioles or on veins. The α2-adrenergic receptors bind both norepinephrine released by the sympathetic postganglionic fibers and epinephrine released by the adrenal medulla.
Common effects of α2-adrenergic receptors include suppression of release of norepinephrine by negative feedback, transient hypertension followed by sustained hypotension, decrease in heart rate, vasoconstriction of certain arteries, venoconstriction of some veins, decrease of motility of smooth muscles in the gastrointestinal tract, and sedation and analgesia.
Agonists (activators) of the α2-adrenergic receptors are frequently used as sedatives and in the anesthesia where they affect sedation, muscle relaxation and analgesia through effects on the central nervous system (CNS).
Substituted imidazoles and substituted thiazines are α2-adrenergic receptor agonists used in the veterinary medicine in sedation, analgesia and premedication, and in humans for similar purposes in intensive care. The activation of α2-adrenergic receptors located outside the CNS, such as postsynaptically located receptors on the vascular smooth muscle cells, induces vasoconstriction resulting in hypertension and significantly reduced heart rate, whereby the oxygen delivery to tissues is reduced.
The effect of substituted imidazoles and substituted thiazines is based on the activation of presynaptic α2-adrenergic receptors located in brains, which causes sedation, analgesia, and decrease of level of consciousness and fear.
Clonidine, romifidine, medetomidine, dexmedetomidine and detomidine are examples of such substituted imidazoles; xylazine is an example of substituted thiazines, useful as α2-adrenergic agonists.
Medetomidine, a rasemic mixture of dexmedetomidine and levomedetomidine, is a popular sedative and pre-anesthetic drug used in small animal practice. Medetomidine administration is associated with significant alterations in cardiovascular functions, such as dramatic increase in arterial blood pressure, in systemic and pulmonary vascular resistance, and in myocardial workload after IV administration. Further, reduction in heart rate and in cardiac output decrease global Do2 (oxygen delivery) by at least 50%. Further adverse effects, such as vasoconstriction, bradycardia and decreased respiratory rate are typically caused by medetomidine. In some cases the level and quality of sedation and analgesia may not be sufficient and thus medetomidine may be combined with opioids, such as butorphanol, which has pure κ-agonist, partial μ-agonist and δ-agonist properties.
Dexmedetomidine, the pharmacologically active isomer of medetomidine, has similar side effects to medetomidine, such as vasoconstriction, acute α2-adrenoceptor agonist induced bradyarrhythmias and decreased respiratory rate. In dogs, both dexmedetomidine and medetomidine produce dose dependent degree of sedation, higher doses will prolong the sedative effects.
Detomidine is a α2-adrenergic agonist producing dose-dependent sedative and analgesic effects. Due to inhibition of the sympathetic nervous system it also has cardiac and respiratory effects and an antidiuretic action. After administration to a horse, short period of reduced coordination is characteristically followed by immobility and a firm stance with front legs spread. Following administration there is an initial increase in blood pressure, followed by bradycardia and second degree atrioventricular blocks. The horse commonly sweats to excess, especially on the flanks and the neck.
Detomidine is typically used for sedation and anesthetic premedication in horses and other large animals, commonly combined with butorphanol for increased analgesia and depth of sedation. It may also be used in conjunction with ketamine for intravenous anesthesia of short duration.
Further, re-sedation may occur, typically after 0.5-1 h after an animal has received a α2-adrenoceptor antagonist, such as atipamezole for reversing sedative effect of the α2-adrenoceptor agonist, such as medetomidine.
Several approaches have been studied to minimize the adverse effects of α2-adrenergic agonists, including the dose-dependency of the cardiovascular alterations and the effects of co-administration of anticholinergic agents.
IV administration of an experimental compound MK-467 (known also as L-659,066) has been suggested to attenuate the peripheral vascular effects of the α2-adrenergic agonists.
MK-467 overdose may cause adverse effects such as increase in the heart rate and cardiac index or reduction of blood pressure.
Effects of MK-467 on the hemodynamic changes induced by medetomidine administration in conscious dogs were studied in Enouri S et al, AJVR, Vol 69, No 6, (2008) 728-736. 0.2 mg/kg of MK-467 was administrated IV as pretreatment, and ten minutes after the administration the dogs received 10 μg/kg dose of medetomidine. Premedication with MK-467 prior to sedation with medetomidine reduced negative cardiovascular alterations induced by medetomidine administration in dogs.
Pagel P et al, J. Cardiothor. Vasc. Anaest., Vol 12, No 4, (1998) 429-434, describes premedication (IV) of dogs with 0.1, 0.2 and 0.4 mg/kg of MK-467, followed after 30 min by administration (IV) of 5 μg/kg dose of dexmedetomidine. MK-467 dose-dependently induced reduction in systemic vascular resistance coupled with an increase in heart rate and cardiac output, resulting in stable mean arterial pressures.
The effects of three doses of MK-467 (250, 500 and 750 μg/kg) in combination of 10 μg/kg of dexmedetomidine (IV) on bispectral index (BIS) and clinical sedation in dogs were evaluated in Restitutti F et al, Vet. Anaest. Analg. Vol 38, (2011) 415-422. BIS is used for monitoring sedation and loss of consciousness during anesthesia. Dexmedetomidine decreased BIS-values and MK-467 increased BIS-values especially with higher doses.
Influence of different doses of MK-467 on plasma concentrations of dexmedetomidine in dogs were evaluated in Honkavaara J et al, J Vet. Pharmacol. Therap. (2011) 38, 332-337. Dexmedetomidine 10 μg/kg with 250, 500 or 750 μg/kg and MK-467 (IV) were used. MK-467 dose-dependently attenuated dexmedetomidine induced increase in systemic vascular resistance and blood pressure and the consequent reductions in heart rate and cardiac index.
Cardiopulmonary effects of MK-467 in dogs sedated with medetomidine and butorphanol via IV and IM administration was studied in Salla K et al, Vet. Anaest. Analg. (2014) doi:10.1111/vaa.12158. MK-467 attenuated the cardiovascular effects of medetomidine-butorphanol combination after IV and IM administration.
Intravenous administration of sedative drugs may be a challenge to fractious or uncooperative animals. Thus, in many cases it is preferable to administer sedatives intramuscularly.
Medetomidine is used as sedative or pre-medicament in small animal medicine, and it can be administered intravenously, intramuscularly and subcutaneously (SC). When compared to IV administration, in IM or SC administration of medetomidine it typically takes more time before the sedation of the animal is sufficient for starting the procedure, operation etc. due to the need of absorption of active ingredients to circulation. It takes more of the veterinary's time and less patients can be treated daily. The problem is similar with other substituted imidazoles and substituted thiazines.
Rolfe et al, AJVR, 73(5), (2012) 587-94, describes the use 20 μg/kg of medetomidine, IM, alone or concurrently with MK-467 (0.4 mg/kg, IM), and 10 μg of medetomidine/kg, IV, alone or concurrently with MK-467 (0.2 mg/kg, IV), in dogs in a randomized crossover study. Concurrent administration was carried out in separate syringes at different locations. Heart rate (HR), mixed-venous partial pressure of oxygen (Pvo(2)), and cardiac index (CI) were significantly lower and mean arterial blood pressure (MAP), systemic vascular resistance (SVR), and oxygen extraction ratio (ER) were significantly higher after administration of medetomidine IM or IV, compared with baseline values. Administration of medetomidine and MK-467 IM caused a significantly higher heart rate, CI, and Pvo(2) and significantly lower MAP, SVR, and ER for 60 to 90 minutes than did IM administration of medetomidine alone. Administration of medetomidine and MK-467 IV caused a significantly higher CI and Pvo(2) and significantly lower MAP, SVR, and ER for 45 to 90 minutes than did IV administration of medetomidine alone. No significant difference in sedation was noticed.
Parenteral extravascular administration is commonly used in administration of sedatives in animals. However, it typically takes more time before the full sedative effect is reached than after IV route, which also increases the total time needed for carrying out the desired operation or procedure. Further, it also takes more time before the subject is recovered from the sedation.